BACKGROUND: In our recent studies, alternative splicing has been shown to have a major role in inflammation and autoimmune muscle diseases. AIM: To examine the novel hypothesis that the expression of an essential alternative splicing factor, alternative splicing factor 2 (ASF/SF2), is modulated in muscle inflammation. METHODS: ASF/SF2 expression in muscle biopsy samples from eight patients with inflammatory myopathy and six non-myositic controls was determined by using western blot with anti-ASF/SF2 antibodies. To further elucidate the mechanism of reduced ASF/SF2 expression in inflamed muscle, differentiated C2C12 myotubes were stimulated with proinflammatory cytokine tumour necrosis factor alpha (TNFalpha), followed by western blot analysis of ASF/SF2 expression. RESULTS: ASF/SF2 expression in the muscle biopsy samples from patients with inflammatory myopathy was found to be lower (mean of relative densitometric units 41.1 (2SD 20.7)) than that of the non-myositic controls (mean of relative densitometric units 76.7 (39.6); p<0.05). In addition to this, ASF/SF2 expression was seen to be significantly down regulated (sevenfold) in C2C12 myotubes compared with expression variations in the beta-actin control (0.62-fold; mean 1.22 (0.40); p<0.05). CONCLUSION: Collectively, it is shown, for the first time, that alternative splicing factor ASF/SF2 is down regulated in autoimmune inflammatory myositis-potentially via a TNFalpha-mediated pathway. The development of (1) novel autoantigen isoform microarrays for disease diagnosis and prognosis; (2) novel autoantigen-tolerising treatments for autoimmune diseases; and (3) novel splicing-redirection treatments can be facilitated by the ongoing study of alternative splicing of autoantigen transcripts.
BACKGROUND: In our recent studies, alternative splicing has been shown to have a major role in inflammation and autoimmune muscle diseases. AIM: To examine the novel hypothesis that the expression of an essential alternative splicing factor, alternative splicing factor 2 (ASF/SF2), is modulated in muscle inflammation. METHODS:ASF/SF2 expression in muscle biopsy samples from eight patients with inflammatory myopathy and six non-myositic controls was determined by using western blot with anti-ASF/SF2 antibodies. To further elucidate the mechanism of reduced ASF/SF2 expression in inflamed muscle, differentiated C2C12 myotubes were stimulated with proinflammatory cytokine tumour necrosis factor alpha (TNFalpha), followed by western blot analysis of ASF/SF2 expression. RESULTS:ASF/SF2 expression in the muscle biopsy samples from patients with inflammatory myopathy was found to be lower (mean of relative densitometric units 41.1 (2SD 20.7)) than that of the non-myositic controls (mean of relative densitometric units 76.7 (39.6); p<0.05). In addition to this, ASF/SF2 expression was seen to be significantly down regulated (sevenfold) in C2C12 myotubes compared with expression variations in the beta-actin control (0.62-fold; mean 1.22 (0.40); p<0.05). CONCLUSION: Collectively, it is shown, for the first time, that alternative splicing factor ASF/SF2 is down regulated in autoimmune inflammatory myositis-potentially via a TNFalpha-mediated pathway. The development of (1) novel autoantigen isoform microarrays for disease diagnosis and prognosis; (2) novel autoantigen-tolerising treatments for autoimmune diseases; and (3) novel splicing-redirection treatments can be facilitated by the ongoing study of alternative splicing of autoantigen transcripts.
Authors: R Brouwer; G J Hengstman; W Vree Egberts; H Ehrfeld; B Bozic; A Ghirardello; G Grøndal; M Hietarinta; D Isenberg; J R Kalden; I Lundberg; H Moutsopoulos; P Roux-Lombard; J Vencovsky; A Wikman; H P Seelig; B G van Engelen ; W J van Venrooij Journal: Ann Rheum Dis Date: 2001-02 Impact factor: 19.103
Authors: K Nagaraju; N Raben; L Loeffler; T Parker; P J Rochon; E Lee; C Danning; R Wada; C Thompson; G Bahtiyar; J Craft; R Hooft Van Huijsduijnen; P Plotz Journal: Proc Natl Acad Sci U S A Date: 2000-08-01 Impact factor: 11.205
Authors: Zeyu Xiong; Yan Yan; Enli Liu; Richard T Silver; Srdan Verstovsek; Fan Yang; Hong Wang; Josef Prchal; Xiao-Feng Yang Journal: Clin Immunol Date: 2006-11-17 Impact factor: 3.969
Authors: Tan Zhang; Seung Jun Choi; Zhong-Min Wang; Alexander Birbrair; María L Messi; Jian-Ping Jin; Anthony P Marsh; Barbara Nicklas; Osvaldo Delbono Journal: J Gerontol A Biol Sci Med Sci Date: 2013-12-24 Impact factor: 6.053